Systemic Delivery of Small Interfering RNA Therapeutics: Obstacles and Advances

Abstract

RNA interference (RNAi) has emerged as a critical tool for genetic therapeutics. Within the last two decades, there have been extensive investigations in the systemic delivery of these drugs but the obstacles in in vivo delivery have possessed a great difficulty in their administration. These developments led to the advances in systemic administration with designing and incorporation of various drug carriers, including bioconjugate systems, polymeric complexes, organic and inorganic nanoparticles. However, successful translation of these drug delivery systems for the clinical application has still been a great setback for these class of pharmaceutics. In order to improve their competency and applicability, systemic evaluation of currently available carrier systems is required. In this review, we focus on the obstacles in the systemic administration of small interfering RNAs (siRNAs) and the advances with various carrier systems to overcome the limitations of these obstacles. General obstacles in siRNA delivery have been discussed with major emphasis on the barriers at different stages of systemic administration. Then, advances in their application for targeted delivery with rationally designed carrier systems such as bioconjugates, polymeric complexes, and nanoparticles have been introduced. Lastly, we discuss the progress and state of clinical studies of siRNA therapeutics with perspectives of clinical potential.